PROJECT SUMMARY/ABSTRACT Dilated cardiomyopathy (DCM) defined as an enlarged left ventricle with systolic dysfunction is a leading cause of heart failure and cardiac transplantation. Sudden cardiac death accounts for ~35% of deaths in DCM, of which a significant number of the reported cases are triggered by episodes of emotional stress. Additionally, the incidence of DCM is three times greater in men than women, with reduced levels of androgens associated with poor outcomes in men with heart diseases. Despite the high prevalence and health burden, little is known about the underlying mechanisms that lead to the unexpected premature mortality in DCM, especially in males. The paraventricular nucleus of the hypothalamus (PVN) is a key cardiovascular forebrain nucleus that mediates the stress response under normal conditions and contributes to the overactivity of the sympathetic nervous system in heart failure. Angiotensin II (AngII), the excitatory component of renin-angiotensin system (RAS), and proinflammatory cytokines acting within the brain contribute to the neurohumoral excitation, cardiac remodeling and myocardial electrical instability in heart failure. Our robust preliminary results indicate that acute stress induced by social defeat decrease blood pressure, evoke ventricular arrhythmias and lead to sudden death in male, but not female, sarcoglycan delta deficient (Sgcd-/-) mouse model of DCM. Thus, our central hypothesis is that in DCM, the effects of emotional stress are superimposed upon a basal state of neurohumoral excitation which differ according to sex. We propose that while increased sympathetic outflow would normally cause hypertension, in DCM males with compromised cardiac function and reduced cardiac output, it results in hypotension, arrhythmias and sudden death. We will further determine how the reduced androgens in the DCM males contribute to their vulnerability, while estrogens in the DCM females protect against stress-induced mortality. We will test these novel hypotheses with state-of-the art physiological and molecular approaches in the ubiquitous and cardiac-specific Sgcd-/- mice, in the following two specific aims. Aim 1: To test the hypothesis that stress-induced augmentation of RAS activity and inflammation in the PVN precipitates an exaggerated neurohumoral response in males with DCM, leading to hypotension, arrhythmias and sudden death. Aim 2: To test the hypothesis that the sex hormones modulate RAS activity and inflammation in the PVN, contributing to the increased susceptibility of males with DCM to stress-induced sudden death. These studies will define underlying mechanisms of stress-mediated sudden death in male mice with DCM, and identify novel therapeutic target(s) that will enable discoveries from basic science to be translated into clinical practice for dilated cardiomyopathy and heart failure.